Powdery iodine complexes

ABSTRACT

Complexes in powder form of iodine and a crosslinked polymer based on N-vinyl compounds are obtainable by dry heating of iodine and a polymer which is obtained by polymerization of monovinyl compounds (monomers A) whose vinyl group is bonded to a nitrogen atom of a nitrogen-containing heterocycle, in the presence of from 0.5 to 10% by weight, based on the monomers (A), of a compound (B) of the formula I;                    
     where A is —CH— or a nitrogen atom, and n is 2 or 3. The complexes are suitable for producing antidiarrheals.

The present invention relates to complexes in powder form of iodine anda crosslinked polymer based on N-vinyl compounds, obtainable by dryheating of iodine and a polymer which is obtained by polymerization ofmonovinyl compounds (monomers A) whose vinyl group is bonded to anitrogen atom of a nitrogen-containing heterocycle, in the presence offrom 0.5 to 10% by weight, based on the monomers (A), of a compound (B)of the formula I;

where A is —CH— or a nitrogen atom, and n is 2 or 3.

The invention furthermore relates to a process for preparing suchcomplexes and to the use thereof for producing medicines for diarrhea.

It is known that crosslinked PVP, just like soluble PVP, forms complexeswith iodine. The iodine is more firmly bound to the insoluble carrierthan to the soluble one. Nevertheless, the amount of free iodine issufficient in contact with moisture, eg. wound discharge and other bodyfluids, to kill microorganisms (cf., for example, WO 92/04031).

Processes for preparing crosslinked PVP-iodine are disclosed, forexample, in U.S. Pat. No. 3,136,755 and U.S. Pat. No. 3,907,720.However, neither process leads to stable, uniform, free-flowing powders.Although U.S. Pat. No. 5,152,987 describes the preparation of acrosslinked PVP-iodine in the form of free-flowing powders, in this caseisopropanol is used as solvent. This may lead to iodinated byproducts,quite apart from the medical, ecological and economic disadvantages ofthe use of organic solvents.

Although FR 2 353 297 describes the preparation of crosslinkedPVP-iodine in the form of free-flowing powders by direct reaction of PVPand iodine, additional process steps are necessary, such as purificationof the polymer by treatment with boiling water and ethanol andsubsequent drying under reduced pressure, so that the process is notvery suitable in practice.

It is an object of the present invention to provide complexes in theform of free-flowing powders of iodine and polymers based onN-vinyllactams which are obtainable in a straightforward manner.

We have found that this object is achieved by the iodine complexesdefined at the outset, a process for the preparation and the usethereof.

Suitable monovinyl compounds (monomers A) are nitrogen heterocycleswhich are substituted on a ring nitrogen atom by a vinyl group, andsuitable monomers (A) are, in particular, selected from the groupconsisting of N-vinyllactams, N-vinylimidazole and N-vinylcarbazole.Suitable N-vinyllactams are 5-, 6- or 7-membered lactams which may alsohave methyl, ethyl or propyl substituents on the ring. PreferredN-vinyllactams are N-vinylpyrrolidone and N-vinylcaprolactam.

The polymers used according to the invention can also be obtained frommixtures of the abovementioned monomers, for example by copolymerizationof from 5 to 80% by weight of N-vinylpyrrolidone and from 20 to 95% byweight of N-vinylcaprolactam.

Further copolymers suitable according to the invention are also thosewhich, besides the monomers (A), also comprise up to 80% by weight ofother monoolefinically unsaturated monomers, especially vinyl esterssuch as vinyl acetate, vinyl propionate or vinyl butyrate, and acrylicacid and/or methacrylic acid and their C₁-C₄-alkyl esters.

Particularly preferred polymers comprise as monomers (A)N-vinylpyrrolidone or mixtures of N-vinylpyrrolidone andN-vinylcaprolactam.

The monomers (A) are polymerized in the presence of crosslinkingcompounds (B) of the general formula I. Particularly suitable compounds(B) are cyclic amides which have another vinyl group besides an N-vinylgroup. Examples of suitable compounds are cyclicN,N′-divinylalkyleneureas such as N,N′-divinylethyleneurea orN,N′-divinylpropyleneurea. Also suitable furthermore areN,N′-divinyl-2-imidazolidone or N-vinyl-3-ethylidene-2-pyrrolidone orN-vinyl-3-ethylidene-2-piperidinone.

The polymers can be prepared by conventional processes, preferably bypopcorn polymerization.

A suitable process is described, for example, in DE-C 20 59 484, inwhich case the polymerization takes place in aqueous medium in thepresence of iron, an iron alloy which can be attacked by oxygen, orcobalt, zinc or tin.

Also suitable furthermore is the process described in DE-A 22 55 263, inwhich case the polymerization is started in aqueous solution by heatingto 80° C. and completed at the boiling point of the water.

Likewise also suitable is the process, disclosed in DE-C 2437640, ofpolymerization with exclusion of oxygen in the presence of an α- orβ-ketocarboxylic acid or of a corresponding methyl or ethyl ester.

The polymers can preferably be prepared by the process described in DE-C24 37 629, in which case the polymerization is carried out withexclusion of oxygen in the presence of from 0.05 to 2% by weight of asulfur compound with a valency of less than 6. Suitable sulfur compoundsare selected from the group of sulfites, pyrosulfites, dithionites,sulfoxylates and sulfides, with the corresponding sodium saltspreferably being employed.

The described processes can be carried out in the absence ofconventional free-radical donors in aqueous solution.

The polymers employed according to the invention to prepare thecomplexes are essentially insoluble, ie. they comprise less than 2% byweight of soluble constituents. Preferred polymers have specific surfaceareas (BET) in the range 0.5-5 m²/g, particularly preferably 0.7-4 m²/g.

To prepare the iodine complexes according to the invention, thecomponents, ie. the elemental iodine and the polymer, are vigorouslymixed dry in the absence of a solvent and heated to from 50 to 150° C.,preferably 70 to 120° C. The mixing and heating normally take place in adouble cone mixer but can also be carried out in turbomixers, screwmixers or air-lift mixers. The duration of heating may depend, interalia, on the size of the batch or on the required iodine content, andthe skilled worker can establish this appropriately in a simple manner.

The freely available iodine content was determined in the examples belowin the following manner.

Determination of the Available Iodine Content

About 2 g of insoluble iodine complex are suspended in 100 ml ofdistilled water in a 250 ml Erlenmeyer flask, acidified with glacialacetic acid and mixed with 25 ml of 0.1 N sodium thiosulfate solution.The mixture is then shaken for about 1 h until the suspension iscompletely decolorized. It is then filtered through a fluted filter,washed with about 50 ml of distilled water and titrated against 0.1 Niodine/potassium iodide solution with starch as indicator to a bluecoloration.

Calculation$\frac{\left( {{{ml}\quad {of}\quad {Na}_{2}S_{2}O_{3}\quad {initially}} - {{iodine}\quad {used}}} \right) \times 127}{{weight} \times 100} = {\% \quad {available}\quad {iodine}}$

Determination of the Partition Coefficient (PC)

1 g of a suspension of the insoluble iodine complex with 1% availableiodine is vigorously shaken with 25 ml of n-heptane at 25° C. in a 50 mlgraduated flask for 10 min. When phase separation has occurred afterstanding for about 2 minutes, the heptane phase is filtered off and itsiodine content is determined by photometry. The iodine content of theaqueous phase is calculated from the difference between the iodinecontent employed and the iodine content in the heptane phase.

The iodine complexes obtainable according to the invention are stable onstorage (no loss of iodine), uniform (no fluctuations in concentration)and free of byproducts for practical purposes, the powder isfree-flowing, is not prone to caking on storage, has a specific surfacearea (BET) of from 0.5 m²/g to 5 m²/g, preferably 0.9 to 4 m²/g, and hasan available iodine content of from 0.5 to 18, preferably 8 to 13, % byweight. They have the great advantage on use that, on the one hand, theiodine is so firmly bound that even oral administration is possiblewithout complications in respect of the thyroid gland, but, on the otherhand, sufficient iodine is released for reliable killing of pathogenicorganisms (bacteria) and viruses. Oral use for diarrhea is thus part ofthe invention. The product acts in two ways: on the one hand it bindsfluid while swelling and, on the other hand, it kills the pathogens.

EXAMPLES 1-11

In the following examples, the components were mixed in a double conemixer.

Abbreviations used:

VP N-vinylpyrrolidone

VCAP N-vinylcaprolactam

The polymers used in the following examples were prepared as describedin Example 1 of DE-A 2437629 and were adjusted to the required specificsurface area (BET) (determined by the DIN 66131-132 method) by milling.

Polymer I:

insoluble PVP, BET=1.5-2 m²/g

Polymer II:

insoluble PVP, BET=0.9 m²/g Polymer III:

insoluble PVP, BET=0.7-0.9 m²/g

Polymer IV:

Polymer obtained by copolymerization of VP and VCAP in the ratio 1:5 byweight similar to Example 1 of DE-A 2437629, BET=1.3 m²/g

Polymer V:

Polymer obtained by copolymerization of VP and VCAP in the ratio 1:1 byweight, BET=0.7 m²/g

1. 249 g of polymer I and 51 g of iodine were mixed at 70° C. for 2 hand at 100° C. for 24 h.

Solids content: 97.7% by weight

Available iodine content: 9.95% by weight

Partition coefficient: 187

2. 451 g of polymer II and 85 g of iodine were mixed at 70° C. for 2 hand at 100° C. for 24 h.

Solids content: 96.9% by weight

Available iodine content: 9.32% by weight

Partition coefficient: 220

3. 60 kg of polymer III and 12.3 kg of iodine were mixed at roomtemperature for 1 h, at 70° C. for 2 h and at 100° C. for 20 h.

Solids content: 97.0% by weight

Available iodine content: 12.0% by weight

Partition coefficient: 173

4. 200 g of polymer III and 41 g of iodine were mixed at roomtemperature for 1 h, at 70° C. for 2 h and at 100° C. for 10 h.

Solids content: 97.5% by weight

Available iodine content: 10.3% by weight

Partition coefficient: 293

5. 451 g of polymer IV and 85 g of iodine were mixed at 70° C. for 2 hand at 100° C. for 24 h.

Solids content: 94.96% by weight

Available iodine content: 7.4% by weight

Partition coefficient: 779

6. 451 g of polymer V and 85 g of iodine were mixed at 70° C. for 2 hand at 100° C. for 24 h.

Solids content: 91.5% by weight

Available iodine content: 10.9% by weight

Partition coefficient: 249.8

7. 451 g of polymer V and 85 g of iodine were mixed at 70° C. for 2 hand at 120° C. for 16 h.

Solids content: 90.5% by weight

Available iodine content: 10.5% by weight

Partition coefficient: 200.8

8. 300 kg of polymer II and 60 kg of iodine were mixed at roomtemperature for 1 h, at 70° C. for 2 h and at 95° C. for 30 h.

Solids content: 97.1% by weight

Available iodine content: 11.02% by weight

Partition coefficient: 220

9. 60 kg of polymer III and 12.3 kg of iodine were mixed at roomtemperature for 1 h, at 70° C. for 2 h and at 105° C. for 10 h.

Solids content: 97.0% by weight

Available iodine content: 11.6% by weight

Partition coefficient: 171

10. 60 kg of polymer III and 12.3 kg of iodine were mixed at roomtemperature for 1 h, at 70° C. for 2 h and at 105° C. for 20 h.

Solids content: 97.0% by weight

Available iodine content: 11.3% by weight

Partition coefficient: 311

11. 60 kg of polymer III and 12.3 kg of iodine were mixed at roomtemperature for 1 h, at 70° C. for 2 h and at 115° C. for 20 h.

Solids content: 97.0% by weight

Available iodine content: 13.3% by weight

Partition coefficient: 290

Formulation of Antidiarrheals

EXAMPLE 12

Complex of Example 1 50 mg Microcrystalline cellulose 5 mg Magnesiumstearate 0.5 mg

EXAMPLE 13

Complex of Example 2 200 mg Insoluble PVP 1800 mg Microcrystallinecellulose 100 mg Silica 100 mg Magnesium stearate 10 mg

The formulations of Examples 12 and 13 are suitable for directtabletting.

EXAMPLE 14

A mixture of 200 mg of a complex from Example 2 and 1800 mg of insolublePVP was subjected with 20 mg of povidone K 90 and 9.1 g of ethanol to awet granulation. After the granules had been dried, 10 mg of magnesiumstearate were added. The formulation can be tabletted under conventionalconditions.

We claim:
 1. A storage stable complex in free-flowing powder form ofiodine and a crosslinked polymer based on N-vinyl compounds, obtainableby dry heating of iodine and a polymer which is obtained bypolymerization of monovinyl compounds (monomers A) whose vinyl group isbonded to a nitrogen atom of a nitrogen-containing heterocycle which isa member selected from the group consisting of N-vinylimidazole, N-vinylcarbazole, N-vinyl-pyrrolidone, and N-vinylcaprolactam and mixturesthereof, and optionally, up to 80% by weight of monoolefinicallyunsaturated co-monomer selected from the group consisting of vinylacetate, vinyl propionate and vinyl butyrate, and acrylic acid and/ormethacrylic acid and their C1-C4-alkyl esters in the presence of from0.5 to 10% by weight, based on the monomers (A), of a compound (B) ofthe formula I;

where A is —CH— or a nitrogen atom, and n is 2 or
 3. 2. A method oftreating diarrhea which comprises administering to a patient in needthereof an effective amount of the complex defined in claim 1.